Methods for stimulating neurite growth with piperidine compounds

Abstract

The present invention relates to methods for stimulating the growth of neurites in nerve cells. The methods comprise treating nerve cells with piperidine compounds alone or in combination with a neurotrophic factor, such as nerve growth factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.

We claim: 
     
       1. A method for stimulating neurite growth in a patient or in an ex vivo nerve cell comprising the step of administering to said patient or said nerve cell a neurotrophic amount of a compound having the formula (I): ##STR6## and pharmaceutically acceptable derivatives thereof, wherein: A is oxygen; R 1 , B and D are independently: hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl-substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl-substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl-substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl-substituted (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, or Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;   wherein any one of the CH 2  groups of said alkyl chain in R 1 , B and D is optionally replaced by O, S, SO, SO 2  or NR;   wherein R is hydrogen, (C1-C4) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl chain to form a ring, and wherein said ring is optionally fused to Ar;   J and K are taken together with the nitrogen and carbon atoms to which they are respectively bound to form a piperidine ring;   Z is O or S;   Y is O or N; wherein   when Y is O, then R 1  is a lone pair and R 2  is selected from Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; and when Y is N, then R 1  and R 2  are independently selected from the group consisting of Ar, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; or R 1  and R 2  are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine;   wherein Ar is a carboxylic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo b!furanyl, benzo b!thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl;   wherein Ar is optionally substituted with one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, --SO 3  H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O- (C1-C6)-straight or branched alkyl!, O- (C3-C4)-straight or branched alkenyl!, O-benzyl, O-phenyl, 1,2-methylenedioxy, --NR 3  R 4 , carboxyl, N-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl, O--Z-, CH 2  --(CH 2 ) q  --Z', O-(CH 2 ) q  --Z', (CH 2 ) q  --Z'--O--Z', or CH═CH--Z';   wherein R 3  and R4 are independently selected from (C1-C6)-straight or branched alkyl, (C3-C6) straight or branched alkenyl or alkynyl, hydrogen or benzyl; or wherein R 3  and R 4  are taken together to form a 5-6 membered heterocyclic ring;   wherein Z' is selected from 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl;   wherein q is 0-2; and     n is 0 or 1.   
     
     
       2. The method according to claim 1, wherein said compound is selected from: (S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;   (S)-1-((3-Trifluoromethylphenyl)-methyl-carbamoyl)piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;   (S)-1-((4-Tert-butylphenyl)-methyl-carbamoyl)piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;   (S)-1-((4-Isopropylphenyl)-methyl-carbamoyl)piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;   (S)-1-(Piperidine-1-carbonyl)-piperidine-2-carboxylic acid 4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl ester;   (S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)piperidine-2-carboxylic acid 4-pyridin-1-yl-1-(3-pyridin-1-yl-propyl)-butyl ester;   (S)-Piperidine-1,2-dicarboxylic acid 1-(3,4,5-trimethoxyphenyl)ester-2-(4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)-butyl)ester;   (S)-1-((3,4,5-Trimethoxyphenyl)-methyl-carbamoyl)piperidine-2-carboxylic acid 1-(2-phenyl-ethyl)-3-phenyl-propyl ester;   4-(Methyl-(2-(1-phenethyl-3-phenyl-propoxycarbonyl)piperidine-1-carbonyl)-amino)-benzenesulfonic acid;   (S)-Piperidine-2-carboxylic acid 1-benzyloxy-methyl-2-benzyloxyethyl ester;   (S)-1-(Methyl-(4-morpholin-1-yl-phenyl)-carbamoyl)piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy-methyl)-ethyl ester;   (S)-1-(Methyl-(4-piperidin-1-yl-phenyl)-carbamoyl)piperidine-2-carboxylic acid 2-benzyloxy-1-(benzyloxy-methyl)-ethyl ester;   (S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy-1-(benzyloxymethyl)-ethyl)ester-1-quinolin-5-yl ester;   (S)-Piperidine-1,2-dicarboxylic acid 2-(2-benzyloxy-1-(benzyloxymethyl)-ethyl)ester-1-pyridin-3-yl ester.   
     
     
       3. The method according to claim 1, wherein, in compound of formula (I), at least one of B or D is independently represented by the formula --(CH 2 ) r  --(X)--(CH 2 ) s  --Ar, wherein r, s, and X are as defined in claim 2. 
     
     
       4. The method according to claim 1, wherein said compound has formula (II) or formula (III): ##STR7## wherein R 1 , R 2 , Y, and Ar are as defined in claim 1, and w is 1 or 2. 
     
     
       5. The method according to any one of claims 3, 4 and 1, wherein Ar is selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 1,2,3,4-tetrahydro- quinolinyl, wherein Ar optionally contains one to three substituents which are independently selected from hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6)-straight or branched alkyl, O- (C1-C6)-straight or branched alkyl!, halogen, SO 3  H, and NR 3  R 4 . 
     
     
       6. The method according to claim 1, wherein said patient is suffering from Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, stroke or ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, peripheral neuropathy, diabetic neuropathy, spinal cord injury or facial nerve crush. 
     
     
       7. The method according to claim 6, further comprising the additional step of administering to said patient a neurotrophic factor either as part of a multiple dosage form with said compound or as a separate dosage form. 
     
     
       8. The method according to claim 7, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin growth factor (IGF) and active truncated derivatives thereof, acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotropic factors CNTF), glial cell-derived neurotropic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5). 
     
     
       9. The method according to claim 8, wherein said neurotrophic factor is nerve growth factor (NGF). 
     
     
       10. The method according to any one of claims 6-9, wherein said patient is suffering from diabetes-associated peripheral neuropathy. 
     
     
       11. The method according to claim 1, wherein said method is used to stimulate ex vivo nerve regeneration. 
     
     
       12. The method according to claim 11, comprising the additional step of contacting said nerve cell with a neurotrophic factor. 
     
     
       13. The method according to claim 12, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin growth factor (IGF) and active truncated derivatives thereof, acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotropic factors (CNTF), glial cell-derived neurotropic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5). 
     
     
       14. The method according to claim 13, wherein said neurotrophic factor is nerve growth factor (NGF).